Novel intermediates in the preparation of 13 - polycarbonalkyl - 17alpha - hydroxy-18,19 - dinorpregn - 4 - en - 3,20 - diones and acylates thereof



United States Patent NOVEL INTERMEDIATES IN THE PREPARATION OF 13 POLYCARBONALKYL 17oz HYDROXY- 18,19 DINORPREGN 4 EN 3,20 DIONES AND ACYLATES THEREOF Daniel M. Teller, King of Prussia, George H. Douglas,

v Paoli, and Herchel Smith, Wayne, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 13, 1967, Ser. No. 675,027

Int. Cl. C07c 169/36; A61k 17/06 US. Cl. 260-397.4 5 Claims ABSTRACT OF THE DISCLOSURE V The present invention is concerned with dl-3-alkoxyl3-polycarbonalkyl-18,19-dinorpregna 3,5 dien-20-ones and dl-3-alkoxy-l7u-hydroperoxy-13-polycarbonalkyl 18, 19-dinorpregna-3,5-dien 20-ones which are usefulintermediates in the synthesis of dl-l7-hydroxy-l3-polycarbonalkyl-1'8,19-dinorpregn-4-ene 3,20-dione, acylates which are pharmacologically useful progestational agents;

The present invention relates to new and novel steroids which are useful intermediates. In particular, the com pounds of the present invention'are useful intermediates in the preparation of dl-17-hydroxy-13-polycarbonalkyl- 18,l9-dinorpregn-4-ene-3,20-dione, acylates which :are pharmacologically eflicacious as progestational agents.

The new and novel-steroidal compounds within the Patented Sept. 2, 1969 purview of the present invention are exemplified by the following structural formula:

wherein R is polycarbonalkyl; R is lower alkyl; and R is selected from the group consisting of hydrogen and alpha hydroperoxy. As employed herein the term lower alkyl is defined to include both branched and straight chain alkyl moieties containing from about one to about eight carbon atoms. Alternatively, by the term polycarbon alkyl is meant an alkyl moiety having from two to about eight carbon atoms. Typical examples of these 0 compounds are:

dl-13-ethyl-3-methoXy 18,19-dinorpregna-3 ,5 -dien--one; dl-l3-ethyl-17a-hydroperoxy 3 methoxy-18,19-dinorpregna-3,5-dien20-one;

dl-3-ethoXy-l3-ethyl-18,19-dinorpregna-3,S-dien-ZO one;

and dl-3-ethoxy-13-ethyl-17a-hydroperoxy-l8,19-dinorpregnav 3,5-dien-20 one.

The preparation of the steroid intermediate compounds of the present invention and their utilization in the synthesis of known progestational agents is schematically depicted by the following reaction sequence:

wherein R and R are defined as above and R is defined as hydrogen or acyl.

The above enol-etherification reaction is conducted by refluxing an appropriate dl-l3-polycarbonalkyl-18,19- dinorpregn-4-ene-3,20-dione (I) in an appropriate solvent, e.g., a dimethoxypropane, dimethylformamide, methanol and p-toluene-sulfonic acid mixture for a period from about one to about six hours.

When the enol-etherification reaction is complete, the resulting dl-3-alkoxy-l3-polycarbonalkyl 18,19 dinorpregna-3,5-dien-20-one (II) is separated by routine recovery procedures, e.g., admixing the reaction mixture with alkaline ice water, extracting with a water-immiscible solvent, e.g. benzene, washing and evaporating the combined extracts and then crystallizing the product (II) by trituration with ether.

The hydroperoxidation reaction is effected by adding a tetrahydrofuran solution of the above prepared dl-3-alkoxy-13-polycarbonalkyl-18,19 dinor pregna3,5-dien-20- one (II) to a solution of an alkali metal in a tertiary alkanol at a temperature below C. and stirring the mixture in an oxygen atmosphere until oxygen uptake is complete. Preferably this reaction is conducted using po tassium metal in t-butanol for a period of about two hours.

When the hydroperoxidation reaction is complete, the resulting dl-3-alkoxy-17ot-hydroperoxy-13-polycarbonalkyl- 18,19-dinorpregna-3,5-dien--one (III) is obtained by conventional recovery procedures. For example, the reaction mixture is neutralized with an acid, e.g., acetic acid, extracted with a water-immiscible solvent, e.g., ethyl acetate, then the combined extracts are washed, dried and concentrated at temperatures below 40 C. to afford the product (III).

The reduction reaction is conducted by contacting the above prepared dl-3-alkoxy-17a-hydroperoxy-13-polycarbonalkyl 18,19 dinorpregna-3,5-dien-20 one (III) with zinc dust in glacial acetic acid for a period of about six to about twenty-four hours.

When the reduction reaction is complete, the resulting dl 17a hydroxy 13 polycarbonalkyl 18,19 dinorpregn-4-ene-3,20-dione (IV) is separated by standard chemical procedures. For example, the reaction mixture is filtered, admixed with a water-immiscible solvent, then the combined extracts are washed with water, an alkaline solution, water and concentrated. Thereafter, the product (IV) may be recrystallized from a suitable solvent, e.g., an ethyl acetate-liquid alkane mixture, ether or dioxane.

The acylation reaction is effected by contacting the above prepared dl-17ot-hydroxy-13-polycarbonalkyl-18,l9- dinorpregn-4-ene-3,20-dione (IV) with an acyl halide, its corresponding acyl anhydride and pyridine at about room temperature for a period of more than twenty-four hours.

When acylation reaction is complete, the resulting dl-3, 17-dihydroxy-13 polycarbonalkyl 18,19 dinorpregna- 3,5-dien-20-one, diacylate (V) is obtained using customary isolation procedures. For example, the reaction mixture is concentrated at a temperature below 45 C., the residue is admixed with water, extracted with a waterimmiscible solvent, the combined extracts are washed with water, an alkaline solution, water, then dried and concentrated.

The hydrolysis reaction is conducted by contacting the above prepared dl-3,17dihydroxy-13-polycarbonalkyl-18, l9-dinorpregna-3,5-dien 20 one, diacylate (V) with an alkanolic solution of an alkali metal hydroxide at tem peratures below 10 C. under an inert atmosphere for a period from about ten minutes to about four hours. Preferably, this reaction is conducted utilizing methanolic potassium hydroxide under a nitrogen atmosphere.

When the above hydrolysis is complete, the resulting dl 17 hydroxy 13 polycarbonalkyl-18,l9-dinorpregn- 4-ene-3,20-dione, acylate (V1) is separated by routine recovery procedures. For example, the reaction mixture is poured into an aqueous alkaline solution, extracted with a water-immiscible solvent, then the organic layer is washed with an aqueous alkaline solution, water, dried and concentrated.

The starting materials in the above process, the dl-l3- polycarbonalkyl-18,19-dinorpregn-4 ene 3,20 diones (I) are prepared by the procedure described in copending US. patent application, Ser. No. 228,384, entitled Steroid Synthesis, filed Oct. 4, 1962, which is a continuation-in-part of Ser. No. 57,904, filed on Sept. 23, 1960 and now abandoned; Ser. No. 91,341 filed on Feb. 24, 1961 and now abandoned; Ser. No. 137,535, filed Sept. 12, 1961 and now abandoned; Ser. No. 195,000, filed May 15, 1962, and now abandoned; and Ser. No. 196,557, filed May 16, 1962 and now abandoned.

The steroid intermediate compounds (III) and (IV) of the present invention are useful in the preparation of dl 17 hydroxy 13 polycarbonalkyl-18,19-dinorpregn- 4-ene-3,20-dione acylates (VI) which are described in copending US. patent application, Ser. No. 628,275, entitled Synthesis of Steroids, filed on Apr. 4, 1967, wherein it is disclosed that these compounds (VI) are physiologically active substances.

These compounds (VI) in standard pharmacological tests have demonstrated oral activity as progestational agents which are useful in the treatment of functional uterine bleeding, amenorrhea, premenstrual tension, dysmenorrhea, habitual absortion, menopausal, syndrome and infertility.

When these dl-17-hydroxy-13-polycarbonalkyl-18,19-dinorpregn-4-ene-3,20-dione acylates (VI) are employed as progestational agents, they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally. For parenteral administration they may be used in the form of a sterile solution containing othersolutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of these dl-17-hydroxy-13-polycarbonalkyl- 18,19-dinorpregn-4 ene 3,20 dione, acylates (VI) will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. Generally, treatment is initiated with small dosages substantially less than th optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a level that is in the range of from about 0.005 mg. to about 0.3 mg. per kilo per day, although as aforementioned variations will occur. However, a dosage level that is in the range of from about 0.01 mg. to about 0.1 mg. per kilo per day is most desirably employed in order to achieve effective results.

The following examples are given by way of illustration and are not to be construed as limitations of this invention, many variations of which are possible without departing from the scope and spirit thereof.

Example I A solution of dl-l3-ethyl-18,l9-dinorpregn-4-ene-3,20- dione (0.20 g.), 2,2-dimethoxypropane (2.0 ml.), N,N- dimethylformamide (2.0 ml.), methanol (0.10 ml.) and p-toluenesulfonic acid (6 mg.) is refluxed for three and a half hours. The solution is cooled, excess solid sodium bicarbonate is added and the mixture poured into ice water. Extraction with benzene, washing the extracts with water and stripping in vacuo yields a gum which crystallizes on tritur'ation with ether. Recrystallization from.

methanol containing a trace of pyridine affords 75 mg. of dl-13-ethyl-3-methoxy-18,19-dinorpregna-3,5-dien-20 one; M.P. 112121 C.;

Ail, 5.86, 6.07, 6.16,'8.54:I.L;.)\133 H 250 m (6 16,500)

Similarly, dl-13-ethyl-18,19-dinorpregn-4-ene-3,20-dione is converted to dl-3-ethoxy-13 ethyl-18,19-dinorpregna-3,

5-dien-20-one.

Example II dl-3-ethoxy-13-propy1-18,19-dinorpregna-3,5-dien-20-one;. dl-13 -butyl-3-methoxy-18,19,dinorpregna-3,5-dien-20-one; dl-3-ethoxy-13-hexyl-18,19,dinorpregna-3,5-dien-20-one;

' and dl-3-butoxy-13-ethyl-18,19-dinorpregna-3,S-dien-ZO-one.

Example III To a solution of potassium metal (1.7 g.) in distilled t-butanol (45 ml.), there is added dl13-ethyl-3-rnethoxy- 18,19-dinorpregna-3,5dien-20-one (1.50 g.) in tetra hydrofuran (15 ml.) at 0 C. The solution is stirred vigorously at 0 C. in an atmosphere of oxygen. "After two hours oxygen uptake-ceases,,at which time 60 percent of the theoretical is absorbed. The solution is neutralized to pH-7 with '1 N acetic acid, ethyl acetate is added and the solution washed with water and dried over anhydrous sodium sulfate. Evaporation at temperatures below 40 Cuinvacuo affords 1.3 g. of crystalline dl-l3-ethy1-17a-hydroperoxy-3-methoxy-18,19-dinor pregna-3,5-dien-20-one;

3.02, 5.85 (shoulder), 5.90, 6.04, 6.14, 8.56 1

In like manner, dl-3-ethoxy-13-ethyl-18,19-dinorpregna- 3,5-dien-20-one is hydroperoxidized to afford dl-3-ethoxy- 13 ethyl 17a hydroperoxy-18,l9-dinorpregna-3,5-dien- 20-one.

max.

Example IV To a solution of sodium metal (2.4 g.) in distilled t-butanol (90 ml.), there is added dl-3-methoxy-13-propyl- 18,19-dinorpregna-3,5-dien-20-one (3.0 g.) in tetrahydrofuran (30 ml.) at temperatures below 10 C. The solution is stirred vigorously below 10 C. in an atmosphere of oxygen. After about two hours oxygen uptake ceases. The solution is then neutralized to pH 7 with 1 N acetic acid, ethyl acetate is added and the solution washed with water and dried over anhydrous sodium sulfate. Evaporation at less than 40 C. in vacuo affords ell-17ahydroperoxy 3 methoxy 13-propy1-18,19-dinorpregna- 3,5-dien-20-one.

In like manner, the other compounds of Example II are hydroperoxidized to yield:

dl-3-e thoxy-17a-hydroperoxy-13-propy1-18,19-dinorpregna-3,5-dien-20-one;

dl-13-butyl-17 a-hydroperoxy-3-methoxy-18,19-dinorpregna-3,5-dien-20-one;

dl-3-ethoxy-17a-hydroperoxy-13-hexyl-18-19-dinorpregna- 3,5-dien-20-one; and

dl-3-butoxy-13-ethyl-17a-hydroperoxy-18,19-dinorpregna- 3,5 -dien-20-one.

- Example V The crude dl-l3-ethyl-17a-hydroperoxy-3-methoxy-18, l9-dinorpregna-3,5-dien-20-one (1.3 g.) from Example III is stirred for fourteen hours at room temperature in glacial acetic acid (41.5 ml.) containing zinc dust (2.5 g.). The mixture is filtered through Celite, diluted with benzene and the solution washed with water, saturated aqueous sodium bicarbonate, water and stripped in vacuo giving 0.78 g. of product. Two recrystallizations from ethyl acetate/hexane affords 0.20 g. of dl-13-ethyl-17ahydroxy-18,19-dinorpregn-4-ene-3,20-dione, M.P. 208,- 211 0.;

mg; 3.02, 5.86, 6.04, 6.19 0; x512? 240 mu (6 16,900)

Analysis.Calculated for C H O C, 76.32; H, 9.15. Found: C, 76.61; H, 9.22.

In the same way, dl-3-ethoxy-13-ethy1-17u-hydroxyperoxy-lS,19-dinorpregna-3,5-dien-20-one is converted to dl 13 ethyl 17a-hydroxy-l8,19-dinorpregn-4-ene-3,20- dione.

Example VI The crude dl-17a-hydroperoxy-3-methoxy-13-propyl-18, 19-dinorpregna-3,5-dien-20-one (2.6 g.) from ExampleIV is stirred for twenty hours at room temperature in glacial acetic acid (83 ml.) containing zinc dust (5.0 g.). The mixture is filtered through Celite, diluted with toluene and the solution washed with water,.saturated aqueous sodium bicarbonate, water and stripped in vacuo yielding dl 17oz hydroxy-13-propyl-18,19-dinorpregn-4-ene-3,20- dione.

Repeating the above procedure-with the other com-. pounds of Example IV, the following are prepared:

dl-13-butyl-17a-hydroxy-18 l9-dinorpregn-4-ene-3,20-

dione; and dl-l3-hexyl-l7a-hydroxy l8,19-dinorpregn-4-ene-3,20-

dione.

Example VII Similarly, dl-l3-ethyl-17a-hydroxy-l8,19-dinorpregn-4- ene-3,20-dione is reacted with propionyl chloride and propionyl anhydride to afford a l-13-ethyl-3,17-dihydroxy- 18,l9-dinorpregna-3,5-dien-20-one, dipropionate.

Example VIII To a mixture of dl-17a-hydroxy-13-propyl18,19-dinorpregn-4-ene-3,20-dione (2.40 g.) in butyryl chloride (19.2 ml.), there is added with vigorous stirring, butyryl anhydride (38.4 ml.) and then pyridine (1.9 ml.). The mixture is warmed to effect solution, then stirred at room temperature for twenty-four hours. The solvents are stripped off in vacuo 45 C.) giving a solid residue. The residue is dissolved in ether, washed with water, saturated aqueous sodium bicarbonate, water dried over anhydrous sodium sulfate and stripped in vacuo to afford dZ 3,17 dihydroxy 13-propyl-18,19-dinorpregna-3,5- dien-20-one, dibutyrate.

Repeating the above reaction to react the other compounds of Example VI with appropriate acylhalides and anhydrides the following compounds are obtained:

7 dl-13-butyl-3,17-dihydroxy-18,19-dinorpregna-3,5-dien- 20-one, dibenzoate; and dl-l3-hexyl-3,17-dihydroxy-18,19-dinorpregna-3,5-dien- 20-one, diacetate.

Example DC The crude dl-13-ethy1-3,17-dihydroxy-18,19-din0rpregna-3,5-dien-20-one, diacetate (1.45 g.) from Example VII is placed in a mixture of tetrahydrofuran (24 ml.), methanol (24 ml.) and methanolic potassium hydroxide (2 percent, 24 ml.) at C. The mixture is stirred under nitrogen at 0 C. for forty-five minutes, poured into saturated aqueous sodium bicarbonate, extracted with ether, the organic layer Washed With saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and stripped in vacuo. The residue crystallizes on trituration With ether. Column chromatography on Grade III Woelm neutral alumina (50 g.) with hexane/benzene (1:1) and recrystallization from ethyl acetate/hexane affords 0.51 g. of dl-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-3,20-dione, acetate; M.P. 194196 C.; REE; 5.78, 5.83, 6.00, 6.20, 7.97n and no hydroxyl absorption; A323? 240 me (6 16,900)

Analysis.Calcd. for C H O C, 74.16; H, 8.66. Found: C. 74.29; H, 8.39.

In like manner, dl-l3-ethyl-3,17-dihydroxy-18,19-dinorpregna3,5-dien-20-one, dipropionate is converted to dl- 13-ethyl-17-hydroxy-18,19-dinorpregn 4 ene-3,20-dione, propionate.

Example X The crude dl-13,17-dihydroxy l3 propyl-l8,19-dinorpregna3-5-dien-20-one, dibutyrate (2.9 g.) from Example VIII is placed in a mixture of tetrahydrofuran (50 ml.), methanol (25 ml.) and methanolic sodium hydroxide (2 percent, 50 ml.) below C. The mixture is stirred under nitrogen at 0 C. for four hours, poured into saturated aqueous sodium bicarbonate, extracted with ether, the organic layer washed with saturated aqueous sodium bicarbonate, water, dried over anhydrous sodium sulfate and stripped in vacuo. The residue crystallizes on trituration with ether to afford dl-17-hydroxy-13-pr0pyl-18,19- dinorpregn-4-ene-3,20-dione, butyrate.

When the above hydrolysis is repeated on the other wherein R is polyacrobonalkyl and R is lower alkyl.

2. A compound as described in claim 1 which is: til- 13 ethyl- 17 a-hydroperoxy-3-methoxy-18, 19-dinorpregna- 3,5-dien-20-one.

3. A compound as described in claim 1 which is dl-3- ethoxy 13 ethyl Her-hydroperoxy-18,19-dinorpregna- 3,5-dien-20-one.

4. A compound as described in claim 1 in which is: dl- 17a hydroperoxy 3 methoxy-13-propyl-18,19-dinorpregna3,5-diene-20-one.

5. A compound as described in claim 1 which is: dl- 3 ethoxy a hydroperoxy-13-propyl-18,19-dinorpregna-3,5-dien-20-one.

References Cited UNITED STATES PATENTS 4/1965 Ringold 260239.55

OTHER REFERENCES Chemical Abstracts, vol. 62 1965), 1722 g.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

2 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 5, 9 Dated September 2, 1969 Inventor(s) Daniel M. Teller George H. Douglas and Herchel Smith It is certified that error appears in the. above-identified patent and that said Letters Patent are hereby corrected as shown below:

In column 2, formulae,

R F =0 R C=o l @937 Enol-Etherificatiom l R 0 l Hydroperoxidation :hould read CH 0H C=o Enol-Egherj IIigaJ- j n; C=0 o (I) new) i/Hydroperoxidation In column 8, formula,

C I R C=O C J--ooH 1 OOH should read "polyacrobonalkyl" In column 8, claim 1, line 20,

Should read --p0lycarbonalkyl-- J Signed and scaled this 5th day of May 1970.

:SEAL) \ttus) Lin; Officer LLWW. l l 

